Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:10]2[CH:11]=[C:12]([CH:23]=[CH:24][CH:25]=2)[C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])=[N:6][C:7]=1[CH:8]=O.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.[BH-](O[C:42]([CH3:44])=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C.C(=O)([O-])[O-].[Na+].[Na+]>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:10]2[CH:11]=[C:12]([CH:23]=[CH:24][CH:25]=2)[C:13]([N:15]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:44]2[CH:42]=[CH:25][CH:10]=[CH:5][CH:4]=2)=[O:14])=[N:6][C:7]=1[CH2:8][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1
Reactant: Nc1ncc(-c2cccc(C(=O)NCc3ccccc3)c2)nc1C=O
Reactant: C1COCCN1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: Nc1ncc(-c2cccc(C(=O)N(Cc3ccccc3)c3ccccc3)c2)nc1CN1CCOCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 153.5 %

Procedure:
3-(5-Amino-6-formylpyrazin-2-yl)-N-benzylbenzamide (1.27 g, 3.83 mmol) was dissolved in dichloroethane (30 mL) at 0° C. Morpholine (400 mg, 4.6 mmol), and NaBH(OAc)3 (2.03 g, 9.58 mmol) were added and the reaction was stirred at room temperature for 20 h. The reaction mixture was diluted with saturated sodium carbonate and extracted 3× with ethyl acetate. The combined ethyl acetate layers were dried over sodium sulfate, filtered, and concentrated iii vacuo to afford the product (1.41 g, 88% yield). 1H NMR (400 MHz, d4-CD3OD): δ 8.60 (s, 1H), 8.47 (t, 1H), 8.12 (m, 1H), 7.84 (m, 1H), 7.55 (t, 1H), 7.31-7.89 (m, 4H), 7.23-7.26 (m, 1H), 4.61 (s, 2H), 4.43 (s, 2H), 3.32-4.16 (m, 8H). MS (EI) for C23H25N5O2: 404 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([C@H:25]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)O)[CH2:9][C@:10]([CH3:24])([CH2:21][CH:22]=[CH2:23])[C:11]([NH:13][C@@H:14]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:15]O)=[O:12])[CH:5]=[CH:6][CH:7]=1.N1C(C)=CC=CC=1C.[F:42][C:43]([F:56])([F:55])[S:44]([O:47]S(C(F)(F)F)(=O)=O)(=[O:46])=[O:45].C(OCC)(=O)C>C(Cl)Cl.[O-]S([O-])(=O)=O.[Cu+2]>[O-:47][S:44]([C:43]([F:56])([F:55])[F:42])(=[O:46])=[O:45].[CH2:21]([C@@:10]1([CH3:24])[CH2:9][C@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C@@H:25]([C:27]2[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=2)[N+:13]2[C@@H:14]([C:17]([CH3:20])([CH3:18])[CH3:19])[CH2:15][O:12][C:11]1=2)[CH:22]=[CH2:23]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: C=CC[C@@](C)(C[C@H](c1cccc(Cl)c1)[C@@H](O)c1ccc(Cl)cc1)C(=O)N[C@H](CO)C(C)(C)C
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)[N+]2=C1OC[C@@H]2C(C)(C)C
Product: O=S(=O)([O-])C(F)(F)F
Temperature: 0 °C

Procedure:
To a solution of (S)-2-((2R,3R)-2-(3-chlorophenyl)-3-(4-chlorophenyl)-3-hydroxypropyl)-N—((S)-1-hydroxy-3,3-dimethylbutan-2-yl)-2-methylpent-4-enamide (Example 363, step A, 950 mg, 1.929 mmol) in DCM (19 mL) at −50° C. was added 2,6-lutidine (896 μl, 7.72 mmol) followed by trifluoromethanesulfonic anhydride solution (1M DCM, 4.34 mL, 4.34 mmol). The progress of the reaction was monitored by LC/MS. An additional charge of 450 uL (2 eq) 2,6-lutidine followed by 1.12 eq triflic anhydride (2.16 mmol, 2.16 mL of 1M solution in dichloromethane). The reaction was allowed to warm to 0° C. and then poured into sat. aq. CuSO4 solution. To the mixture was added 100 mL ethyl acetate. The layers were separated and the organic phase was washed with sat. aq. CuSO4. The combined organic layers were concentrated and purified by column chromatography on silica gel (eluent: 20 to 50% acetone in hexanes) to afford the title compound.
Reaction SMILES: [Br:1][CH:2]([CH2:6][CH2:7][N:8]1[C:12](=[O:13])[C:11]([CH3:15])([CH3:14])[N:10]([CH3:16])[C:9]1=[O:17])[C:3]([OH:5])=[O:4].[NH2:18][C@@H:19]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C@@H:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[OH:21].C(OC(C)C)(=O)C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OC)(C)(C)C>[Br:1][C@H:2]([CH2:6][CH2:7][N:8]1[C:12](=[O:13])[C:11]([CH3:15])([CH3:14])[N:10]([CH3:16])[C:9]1=[O:17])[C:3]([OH:5])=[O:4].[NH2:18][CH:19]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[OH:21]
Reactant: N[C@@H](c1ccccc1)[C@H](O)c1ccccc1
Reactant: CN1C(=O)N(CCC(Br)C(=O)O)C(=O)C1(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: COC(C)(C)C
Solvent: CC(=O)OC(C)C
Product: CN1C(=O)N(CC[C@@H](Br)C(=O)O)C(=O)C1(C)C
Product: NC(c1ccccc1)C(O)c1ccccc1
Temperature: 57.5 °C

Procedure:
α-Bromo-3,4,4-trimethyl-2,5-dioxo-1-imidazolidinebutanoic acid (I) (111 g, 362.4 mmol) and (1R,2S)-(−)-2-amino-1,2-diphenylethanol (II) (the chiral amine, 75 g, 351 mmol, Aldrich) and tetrabutylammonium bromide (catalytic nucleophile, 2.4 g) were charged to a flask. I was obtained by/from Aerojet Fine Chemicals (a Division of Gencorp, Rancho Cordova, Calif.). To this was added 3 L of a 1:1 mixture of i-propyl acetate (i-PrOAc) and methyl t-butyl ether (MTBE). The resulting slurry was heated to 55-60° C. for 24 to 48 h. Reaction was deemed complete when the ratio of the diastereomers was ≧94:6 (R:S). The reaction was cooled to room temperature and the diastereomeric salt, (R)-α-bromo-3,4,4-trimethyl-2,5-dioxo-1-imidazolidinebutanoic acid, [R-(R*,S*)]-β-amino-α-phenylbenzeneethanol salt (1:1) (IA), was isolated by filtration. The product cake was washed with 850 mL of MTBE. The MTBE wet product cake was suspended in 1800 mL of MTBE. Water, 1800 mL was added. The pH of the aqueous phase was adjusted to between 1 and 2 with methanesulfonic acid (˜23 mL). The phases were separated and the lower aqueous phase was extracted with MTBE (3×1L). The combined organic phases were washed with water (250 mL). The product, (R)-α-bromo-3,4,4-trimethyl-2,5-dioxo-1-imidazolidinebutanoic acid (IB)was used directly in the next step without isolation. In process yield and quality was 101.0 g, 93.0 M%, 87.4% ee (enantiomeric excess). IB: 1H NMR (CDCl3): δ(ppm)=4.30 (m, 1H), 3.72 (m, 2H), 2.96 (s, 3 H), 2.48 (m, 1H), 2.27 (m, 1H), 1.39 (s, 6H). 13C NMR (CDCl3): δ (ppm)=176.7, 172.2, 155.2, 61.4, 41.7, 36.6, 33.2, 24.4, 21.9, 21.9. IR (KBr): ν (cm−1)=3000 (br), 1740 (s), 1680 (s), 1450 (br), 1250 (s).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH:13]([C:16]#[N:17])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:18]=[N+:19]=[N-:20].[Na+].[Cl-].[NH4+].C(Cl)Cl>CN(C=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH:13]([C:16]2[NH:20][N:19]=[N:18][N:17]=2)[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CC1CCN(C(=O)OCc2ccccc2)C1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCC(c2nnn[nH]2)C1
Temperature: 105 °C
Reaction time: 8 h
Yield: 31.4 %

Procedure:
A mixture of 1.8 g (7.8 mmol) of (R/S)-1-benzyloxycarbonyl-3-cyano pyrrolidine (from Step A), 1.5 g (23 mmol) of sodium azide and 1.25 g (23 mmol) of ammonium chloride in 70 mL of DMF was stirred at 105° C. overnight. After cooling to rt, the reaction was poured into 150 mL of CH2Cl2 and washed with 150 mL of 1N HCl and 2×150 mL of H2O. The organic phase was dried over MgSO4 and concentrated. The residue was purified on a 40M Biotage column using 80:20:1 v/v/v CH2Cl2/EtOAc/HOAc as the eluant to afford 670 mg (31%) of the title compound: RF: 0.23 (80:20:1 v/v/v CH2Cl2/EtOAc/HOAc); 1H-NMR (500 MHz) δ 2.29, 2.48 (2m, 2H), 3.54-4.03 (m, 5H), 5.14-5.24 (m, 2H), 7.30-7.37 (m, 5H), 10.43 (br, 1H).
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:19](=[O:20])[N:18]2[CH:13]1[S:14][CH2:15][N:16]([S:31]([C:34]([F:37])([F:36])[F:35])(=[O:33])=[O:32])[CH:17]2[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:46])C=1>C(Cl)Cl>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:19](=[O:20])[N:18]2[CH:13]1[S:14](=[O:46])[CH2:15][N:16]([S:31]([C:34]([F:35])([F:36])[F:37])(=[O:32])=[O:33])[CH:17]2[C:21]([O:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:22])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(COc1ccccc1)NC1C(=O)N2C1SCN(S(=O)(=O)C(F)(F)F)C2C(=O)OCc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)OCc3ccccc3)N(S(=O)(=O)C(F)(F)F)CS(=O)C12
Reaction time: 0.33 h
Yield: 91.2 %

Procedure:
To a solution of benzyl 7-phenoxyacetamido-8-oxo-3-trifluoromethanesulfonyl-5-thia-1,3-diazabicyclo[4,2,0]octane-2-carboxylate (1.172 g.) in methylene chloride (10 ml.) was added dropwise a solution of m-chloroperbenzoic acid (430 mg.) in methylene chloride (6 ml.) at 0° C. with stirring over a period of 20 minutes, and the mixture was stirred for an additional 15 minutes. The mixture was diluted with methylene chloride and washed with a chilled dilute aqueous solution of sodium bicarbonate and a mixture of a dilute aqueous solution of sodium chloride and an aqueous solution of sodium bicarbonate. Drying over magnesium sulfate and removal of the solent left an amorphous solid (1.2 g.), which was chromatographed on silica gel (17 g.) with methylene chloride and then a mixed solvent of methylene chloride and ethyl acetate as an eluent to give an amorphous solid (1.10 g.) of benzyl 7-phenoxyacetamido-8-oxo-3-trifluoromethanesulfonyl-5-thia-1,3-diazabicyclo[4,2,0]octane-2-carboxylate-5-oxide.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][Br:10])[CH:4]=1.[CH3:11][P:12]([O:16]CC)[O:13][CH2:14][CH3:15].O>CN(C=O)C>[Br:10][CH2:9][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[CH2:2][P:12]([CH3:11])(=[O:16])[O:13][CH2:14][CH3:15]
Reactant: BrCc1cccc(CBr)c1
Reactant: CCOP(C)OCC
Solvent: CN(C)C=O
Solvent: O
Product: CCOP(C)(=O)Cc1cccc(CBr)c1
Temperature: 150 °C
Yield: 44 %

Procedure:
To a solution of α,α′-Bisbromo-m-xylene (7.75 g, 29.38 mmol) in DMF (10 mL) was added diethyl methylphosphonite (2.0 g, 14.69 mmol) via syringe. The mixture was heated to 150° C. for 2 minutes in a microwave. The reaction mixture was poured into water and product extracted with ethyl acetate (3×25 mL). The combined organics were washed with water (2×50 mL) and brine (50 mL), and dried over Na2SO4. Reduced volume in vacuo and purified product by flash column eluting 20-100% ethyl acetate in hexanes to give 1.89 g mg (44%) 65 as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 1.24 (t, 3H), 1.33 (d, 3H), 3.08 (d, 2H), 3.97 (dt, 2H), 4.44 (s, 2H), 7.25 (m, 4H). LCMS: m/z for C11H16BrO2P++H observed 291.0 and 293.0 at 2.09 minutes of a 3.5 minute run, gradient 5-95% CH3CN in H2O.
Reaction SMILES: [O:1]1[CH:6]([C:7]([O-:9])=[O:8])[CH:2]1[C:3]([O-:5])=[O:4].[Ca+2:10].[S:11](=[O:15])(=[O:14])([OH:13])[OH:12]>C(O)(=O)C>[S:11]([O-:15])([O-:14])(=[O:13])=[O:12].[Ca+2:10].[O:1]1[CH:6]([C:7]([OH:9])=[O:8])[CH:2]1[C:3]([OH:5])=[O:4]
Reactant: O=S(=O)(O)O
Reactant: O=C([O-])C1OC1C(=O)[O-]
Agent: [Ca+2]
Solvent: CC(=O)O
Product: O=C(O)C1OC1C(=O)O
Product: O=S(=O)([O-])[O-]

Procedure:
The acid calcium epoxysuccinate obtained by the epoxidation was reacted in acetic acid with the aid of concentrated sulphuric acid to form calcium sulphate and epoxysuccinic acid. For this purpose, 50 g. of acid calcium epoxysuccinate, having a calcium content of 11.9% by weight, and 15 g. of concentrated sulphuric acid were introduced, with stirring, into 300 ml. of glacial acetic acid. The suspension was kept at 20° C. for 2 hours with stirring, and then heated to 70° C. After 2 more hours the reaction was complete and the calcium sulphate was filtered off. The calcium sulphate was washed three times with 30 ml. of glacial acetic acid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]2[CH2:7][CH2:8][N:9]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C@@H:22]([NH2:24])[CH3:23])=[CH:18][CH:17]=3)[CH2:10][C:11]=2[CH:12]=[CH:13][CH:14]=1)=[O:4].[C:25](OC(=O)C)(=[O:27])[CH3:26]>CC(O)=O>[CH3:1][O:2][C:3]([C:5]1[C:6]2[CH2:7][CH2:8][N:9]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([C@@H:22]([NH:24][C:25](=[O:27])[CH3:26])[CH3:23])=[CH:20][CH:21]=3)[CH2:10][C:11]=2[CH:12]=[CH:13][CH:14]=1)=[O:4]
Reactant: COC(=O)c1cccc2c1CCN(Cc1ccc([C@H](C)N)cc1)C2
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: COC(=O)c1cccc2c1CCN(Cc1ccc([C@H](C)NC(C)=O)cc1)C2
Temperature: 25 °C

Procedure:
To 475 mg (1.46 mmol) 2-[4-((S)-1-amino-ethyl)-benzyl]-1,2,3,4-tetrahydro-isoquinoline-5-carboxylic acid methyl ester (example XXXV) in 5 mL AcOH are added 152 μL (1.61 mmol) acetic anhydride and the mixture is stirred at r.t. over night. After that time, the reaction mixture is quenched by the addition of a sat. aq. NaHCO3 solution and extracted three times with EtOAc. The organic layers are combined, dried over MgSO4, filtered and the solvent is removed in vacuo.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[I:34][C:35]1[C:39]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[C:38]([C:45]([O:47][CH2:48][CH3:49])=[O:46])[NH:37][N:36]=1.O[CH2:51][C:52]1([NH:55][C:56](=[O:62])[O:57][C:58]([CH3:61])([CH3:60])[CH3:59])[CH2:54][CH2:53]1>C1COCC1.O>[C:58]([O:57][C:56]([NH:55][C:52]1([CH2:51][N:37]2[C:38]([C:45]([O:47][CH2:48][CH3:49])=[O:46])=[C:39]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[C:35]([I:34])=[N:36]2)[CH2:54][CH2:53]1)=[O:62])([CH3:61])([CH3:59])[CH3:60]
Reactant: CC(C)(C)OC(=O)NC1(CO)CC1
Reactant: CCOC(=O)c1[nH]nc(I)c1C(=O)OCC
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1c(I)nn(CC2(NC(=O)OC(C)(C)C)CC2)c1C(=O)OCC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83.3 %

Procedure:
To a stirred solution of PPh3 (15.52 g, 59.2 mmol) in THF (80.0 mL) cooled to 0° C. was added DIAD (11.50 mL, 59.2 mmol) and the resulting solution stirred at 0° C. for 0.5 h. Intermediate 104C (8.00 g, 23.66 mmol) was added as a solution in THF (20 mL) at 0° C. and stirred at RT for 45 min. A solution of tert-butyl (1-(hydroxymethyl)cyclopropyl)carbamate (5.32 g, 28.4 mmol) in THF (10 mL) at was added at 0° C. and the reaction mixture was allowed to stir at RT for 16 h. The reaction mixture was diluted with water (250 mL) and extracted with EtOAc (2×200 mL). The combined organic layer was washed with brine dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography (220 g REDISEP® column, eluting with 20% EtOAc in hexane). Fractions containing the product were combined and evaporated to afford Intermediate 350A as a pale yellow liquid (10 g, 85%). MS(ES): m/z=508 [M+H]+; 1H NMR (400 MHz, chloroform-d) δ ppm 4.45 (s, 2H), 4.41-4.25 (m, 4H), 1.46 (s, 9H), 1.40-1.30 (m, 4H), 1.24 (s, 3H), 1.03-0.94 (m, 2H), 0.90-0.78 (m, 2H).
Reaction SMILES: [CH2:1]([C:3]1[S:28][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[NH:9][C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].Br[CH2:30][C:31]([C:33]1[CH:42]=[CH:41][C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=1)=[O:32].CN(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[CH2:1]([C:3]1[S:28][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[N:9]([CH2:30][C:31]([C:33]3[CH:42]=[CH:41][C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[CH:34]=3)=[O:32])[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: O=C(CBr)c1ccc2ccccc2c1
Reactant: CCc1cc2c(=O)[nH]c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1cc2c(=O)n(CC(=O)c3ccc4ccccc4c3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 39 %

Procedure:
To a mixture of 4′-[(6-ethyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)methyl]biphenyl-2-carbonitrile (1.5 g), 2-bromo-1-(2-naphthyl)ethanone (1.16 g) and N,N-dimethylformamide (20 mL) was added 60% sodium hydride (0.19 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% potassium hydrogensulfate and then saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as colorless crystals (0.84 g, 39%).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21](O)=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC(N(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O)=CC=1.C(N(CC)C(C)C)(C)C.CN(C)C=O.[CH3:60][C:61]1[O:62][C:63]2[CH:69]=[CH:68][C:67]([NH2:70])=[CH:66][C:64]=2[N:65]=1.Cl>>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21]([NH:70][C:67]4[CH:68]=[CH:69][C:63]5[O:62][C:61]([CH3:60])=[N:65][C:64]=5[CH:66]=4)=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:7])=[O:8])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2ccc3cnc(O)nn23)c1
Reactant: Cc1nc2cc(N)ccc2o1
Agent: Cl
Agent: O=S(=O)(N(c1ccccc1)S(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2cc(Nc3ncc4ccc(-c5cccc(S(=O)(=O)NC(C)(C)C)c5)n4n3)ccc2o1
Temperature: 25 °C
Yield: 40 %

Procedure:
Prepare mixture of N-tert-Butyl-3-(2-hydroxy-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-benzenesulfonamide (75 mg, 0.22 mmol), N-Phenylbis(trifluoromethanesulphonimide) (77 mg, 0.22 mmol), N,N-Diisopropylethylamine (0.113 mL, 0.650 mmol), and N,N-Dimethylformamide (2.0 mL, 26 mmol) and stir at room temperature for half an hour. Add 2-Methyl-benzoxazol-5-ylamine; hydrochloride (52 mg, 0.28 mmol) and stir at 80° C. overnight. The reaction was concentrated, dissolved in 2 mL DMSO, filtered and placed onto the Gilson. The most pure fractions were combined basified with sat. sodium bicarbonate, extracted with DCM, dried filtered, and concentrated to give N-tert-Butyl-3-[2-(2-methyl-benzoxazol-5-ylamino)-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-benzenesulfonamide as a yellow solid (40 mg, 40%). MP=212-214° C. LCMS (E/I+) 477 (M+H). NMR 1H (DMSO-d6)-9.64 (s, 1H), 9.06 (s, 1H), 8.55 (d, 1H, J=8.20 Hz), 8.47 (s, 1H), 8.00 (s, 1H), 7.86 (d, 1H, J=8.06 Hz), 7.68-7.85 (m, 3H), 7.60 (d, 1H, J=8.86 Hz), 7.23 (d, 1H, J=4.86 Hz), 7.01 (d, 1H, J=4.86 Hz), 2.60 (s, 3H), 1.12 (s, 9H).
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([N+]([O-])=O)[C:12]=3[N+:20]([O-:22])=[O:21])[C:7](=[N:26][O:27][CH:28]([CH3:32])[C:29]([OH:31])=[O:30])[C:6]=2[CH:5]=1)([O-:3])=[O:2].[CH3:33][C:34]1[N:38](CCO)[C:37]([N+:42]([O-:44])=[O:43])=[CH:36][N:35]=1.[CH3:45][CH2:46]N=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.C1COCC1>[CH3:33][C:34]1[NH:38][C:37]([N+:42]([O-:44])=[O:43])=[CH:36][N:35]=1.[N+:17]([C:15]1[CH:16]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]2[C:9]3[C:8](=[CH:13][C:12]([N+:20]([O-:22])=[O:21])=[CH:11][C:10]=3[N+:42]([O-:44])=[O:43])[C:7](=[N:26][O:27][CH:28]([CH3:32])[C:29]([O:31][CH2:45][CH3:46])=[O:30])[C:6]=2[CH:14]=1)([O-:19])=[O:18]
Reactant: CCN=C=NCCCN(C)C
Reactant: Cc1ncc([N+](=O)[O-])n1CCO
Reactant: CC(ON=C1c2cc([N+](=O)[O-])cc([N+](=O)[O-])c2-c2c1ccc([N+](=O)[O-])c2[N+](=O)[O-])C(=O)O
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CCOC(=O)C(C)ON=C1c2cc([N+](=O)[O-])cc([N+](=O)[O-])c2-c2c1cc([N+](=O)[O-])cc2[N+](=O)[O-]
Product: Cc1ncc([N+](=O)[O-])[nH]1
Temperature: 25 °C
Reaction time: 6 h
Yield: 106.2 %

Procedure:
The reaction mixture of (+)-2-(2,4,5,6-tetranitro-9-fluorenylideneaminooxy)proprionic acid (223 mg, 0.5 mmol), metronidazole (86 mg, 0.5 mmol), EDCI (133 mg, 0.7 mmol), DMAP (10 mg, 0.1 mmol) and THF (5 ml) was stirred at room temperature for 6 h. THF was then removed under reduced pressure. The residue was dissolved in dichloromethane (50 ml). The organic layer was washed with H2O, 5% Na2CO3, H2O, and brine, and then dried over MgSO4. The solvent was removed under vacuum. The resulting liquid was separated by column chromatography to give 160 mg 2-methyl-5-nitro-1H-imidazole-1-ethyl (+)-2-(2,4,5,7-tetranitro-9-fluorenylideneaminooxy)propionate.
Reaction SMILES: [OH:1][C:2]1[C:3]2[N:4]([C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:9]([CH3:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[F:17][C:18]1[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20]Br.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:17][C:18]1[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20][O:1][C:2]1[C:3]2[N:4]([C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:9]([CH3:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cccc(CBr)c1F
Reactant: CCOC(=O)c1c(C)nc2c(O)cccn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(C)nc2c(OCc3cccc(F)c3F)cccn12
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A suspension of 500 mg of ethyl 8-hydroxy-2-methylimidazo[1,2-a]pyridine-3-carboxylate, 0.35 ml of 2,3-difluorobenzylbromide, and 650 mg of potassium carbonate in 8.6 ml of N,N-dimethylformamide (DMF) was stirred at 60° C. for 1 hour. The reaction mixture was left to be cooled to room temperature and water was then added thereto. The resulting solid was collected by filtration and washed with water. The solid was washed with diisopropyl ether to obtain 650 mg of ethyl 8-[(2,3-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxylate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([OH:13])=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:14][NH:15][CH3:16].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C.O1CCOCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([N:15]([CH3:16])[CH3:14])=[O:13])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CNC
Reactant: O=C(O)C1(c2ccc(Br)cc2)CC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CN(C)C(=O)C1(c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-(4-Bromophenyl)cyclopropanecarboxylic acid (247, 1.00 g, 4.15 mmol) was dissolved in 10 mL DMF and 90 mL dioxane. To it were added dimethylamine (2M in THF, 10.4 mL, 20.7 mmol) and then PyBOP (4.32 g, 8.30 mmol). The mixture was stirred at RT for 2 hours, concentrated in vacuo, diluted with 100 mL EtOAc, washed with water ×3, dried, concentrated in vacuo, and subjected to silica flash column using 0 to 3% MeOH in DCM to isolate 1-(4-bromophenyl)-N,N-dimethylcyclopropanecarboxamide (248) in quantitative yield. It was dissolved in 100 mL dioxane. To the solution were added tert-butyl carbamate (2.91 g, 24.9 mmol), Pd2(dba)3 (760 mg, 0.83 mmol), XantPhos (1.44 g, 2.49 mmol), fine-powder cesium carbonate (8.12 g, 24.9 mmol). The mixture was degassed using N2 stream for 5 min, and stirred under N2 atmosphere at 115° C. for 2 days. It was cooled to RT, concentrated in vacuo, diluted with 200 mL EtOAc, washed with water ×3, dried, concentrated, and subjected to silica flash column to isolate tert-butyl 4-(1-(dimethylcarbamoyl)cyclopropyl)phenylcarbamate (249, 600 mg). It was treated with 20 mL commercial 4N HCl in dioxane at RT for 1.5 hour. The mixture was concentrated in vacuo to dryness to give 1-(4-aminophenyl)-N,N-dimethylcyclopropanecarboxamide (250) as HCl salt.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[C:3](=O)[C:2]2=O.COP([CH2:16][C:17]([C:19]1[C:20]([C:25]([F:28])([F:27])[F:26])=[N:21][N:22]([CH3:24])[CH:23]=1)=O)(=O)OC.O.[NH2:30][NH2:31]>>[CH3:24][N:22]1[CH:23]=[C:19]([C:17]2[CH:16]=[C:3]3[C:2]([CH:1]4[CH2:7][CH:4]3[CH2:5][CH2:6]4)=[N:31][N:30]=2)[C:20]([C:25]([F:28])([F:27])[F:26])=[N:21]1
Reactant: O=C1C(=O)C2CCC1C2
Reactant: NN
Reactant: COP(=O)(CC(=O)c1cn(C)nc1C(F)(F)F)OC
Solvent: O
Product: Cn1cc(-c2cc3c(nn2)C2CCC3C2)c(C(F)(F)F)n1

Procedure:
off-white crystalline solid. MS (EI): 294.2 (M+). Prepared from bicyclo[2.2.1]heptane-2,3-dione, [2-(1-Methyl-3-trifluoromethyl-1H-pyrazol-4-yl)-2-oxo-ethyl]-phosphonic acid dimethyl ester, hydrazine monohydrate.